Combinatorial Chemistry, also known as High Throughput Experimentation, is an emerging area that has impacted various fields. Although still evolving, the procedure is fully established in the pharmaceutical industry. There is increasing interest in applying such techniques in materials science since the combinatorial synthesis method can be a very powerful tool in increasing the rate of experimentation, and therefore, improving the possibility for making discoveries.
The discovery of new materials with novel chemical and physical properties often leads to the development of new and useful technologies. Over forty years ago, for example, the preparation of single crystal semiconductors transformed the electronics industry. Currently, there is a tremendous amount of activity being carried out in the areas of superconductivity, magnetic materials, phosphors, nonlinear optics and high strength materials. Unfortunately, even though the chemistry of extended solids has been extensively explored, few general principles have emerged that allow one to predict with certainty composition, structure and reaction pathways for the synthesis of such solid state compounds. Importantly, it is difficult to predict a priori the physical and chemical properties a particular composition and structure will possess.
Clearly, the preparation of new materials with novel or desired chemical and physical properties is at best happenstance with our current level of understanding. Consequently, the discovery of new materials is limited by the ability to synthesize and analyze new compounds or compositions. As such, there exists a need in the art for a more efficient, economical and systematic approach for the synthesis of novel materials and for the screening of such materials for useful properties.
One of the processes whereby nature produces molecules having novel functions involves the generation of large collections (libraries) of molecules and the systematic screening of those libraries for molecules having a desired property. An example of such a process is the humoral immune system which in a matter of weeks sorts through some 1012 antibody molecules to find one which specifically binds a foreign pathogen (Nisonoff, et al., The Antibody Molecule (Academic Press, New York, 1975)). This notion of generating and screening large libraries of molecules has recently been applied to the drug discovery process. The discovery of new drugs can be likened to the process of finding a key which fits a lock of unknown structure. One solution to the problem is to simply produce and test a large number of different keys in the hope that one will fit the lock.
Using this logic, methods have been developed for the synthesis and screening of large libraries up to 1014 molecules) of peptides, oligonucleotides and other small molecules. Geysen, et al., for example, have developed a method wherein peptide syntheses are carried out in parallel on several rods or pins (see, J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference). Generally, the Geysen, et al. method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. In addition to the Geysen, et al. method, techniques have recently been introduced for synthesizing large arrays of different peptides and other polymers on solid surfaces. Pirrung, et al. have developed a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques (see, U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070, incorporated herein by reference. In addition, Fodor, et al. have developed, among other things, a method of gathering fluorescence intensity data, various photosensitive protecting groups, masking techniques, and automated techniques for performing light-directed, spatially-addressable synthesis techniques (see, Fodor, et al., PCT Publication No. WO 92/10092, the teachings of which are incorporated herein by reference).
Using these various methods, arrays containing thousands or millions of different elements can be formed (see, U.S. Pat. No. 5,424,186, the teachings of which are incorporated herein by reference). As a result of their relationship to semiconductor fabrication techniques, these methods have come to be referred to as “Very Large Scale Immobilized Polymer Synthesis,” or “VLSIPS™ technology. Such techniques have met with substantial success in, for example, screening various ligands such as peptides and oligonucleotides to determine their relative binding affinity to a receptor such as an antibody.
U.S. Pat. No. 5,985,356, issued Nov. 16, 1999, the entire content of which is herein incorporated by reference, discloses the combinatorial synthesis for making and testing an array of novel materials. This patent provides methods and apparatus for the preparation and use of a substrate having an array of diverse materials in predefined regions thereon. A substrate having an array of diverse materials thereon is prepared by delivering components of materials to predefined regions on the substrate, and simultaneously reacting the components to form at least two materials. Materials which can be prepared using the methods and apparatus of the present invention include, for example, covalent network solids, ionic solids and molecular solids. More particularly, materials which can be prepared include inorganic materials, intermetallic materials, metal alloys, ceramic materials, organic materials, organometallic materials, non-biological organic polymers, composite materials (e.g., inorganic composites, organic composites, or combinations thereof), etc. Once prepared, these reaction products can be screened in parallel or sequentially for useful properties including, for example, electrical, thermal, mechanical, morphological, optical, magnetic, chemical and other properties. As such, the patented invention provides methods and apparatus for the parallel synthesis and analysis of novel materials having new and useful properties.
In one embodiment of U.S. Pat. No. 5,985,356, a first component of a first material is delivered to a first region on a substrate, and a first component of a second material is delivered to a second region on the same substrate. Thereafter, a second component of the first material is delivered to the first region on the substrate, and a second component of the second material is delivered to the second region on the substrate. The process is optionally repeated, with additional components, to form a vast array of components at predefined, i.e., known, locations on the substrate. Thereafter, the components are simultaneously reacted to form at least two materials. The components can be sequentially or simultaneously delivered to predefined regions on the substrate in any stoichiometry, including a gradient of stoichiometries, using any of a number of different delivery techniques.
In another embodiment, a method is provided for forming at least two different arrays of materials by delivering substantially the same reaction components at substantially identical concentrations to reaction regions on both first and second substrates and, thereafter, subjecting the components on the first substrate to a first set of reaction conditions and the components on the second substrate to a second set of reaction conditions. Using this method, the effects of the various reaction parameters can be studied on many materials simultaneously and, in turn, such reaction parameters can be optimized. Reaction parameters which can be varied include, for example, reactant amounts, reactant solvents, reaction temperatures, reaction times, the pressures at which the reactions are carried out, the atmospheres in which the reactions are conducted, the rates at which the reactions are quenched, the order in which the reactants are deposited, etc.
In the delivery systems of the patented invention, a small, precisely metered amount of each reactant component is delivered into each reaction region. This may be accomplished using a variety of delivery techniques, either alone or in combination with a variety of masking techniques. For example, thin-film deposition in combination with physical masking or photolithographic techniques can be used to deliver various reactants to selected regions on the substrate. Reactants can be delivered as amorphous films, epitaxial films, or lattice and superlattice structures. Moreover, using such techniques, reactants can be delivered to each site in a uniform distribution., or in a gradient of stoichiometries. Alternatively, the various reactant components can be deposited into the reaction regions of interest from a dispenser in the form of droplets or powder. Suitable dispensers include, for example, micropipettes, mechanisms adapted from ink-jet printing technology, or electrophoretic pumps.
Once the components of interest have been delivered to predefined regions on the substrate, they are reacted using a number of different synthetic routes to form an array of materials. The components can be reacted using, for example, solution based synthesis techniques, photochemical techniques, polymerization techniques, template directed synthesis techniques, epitaxial growth techniques, by the sol-gel process, by thermal, infrared or microwave heating, by calcination, sintering or annealing, by hydrothermal methods, by flux methods, by crystallization through vaporization of solvent, etc. Thereafter, the array can be screened for materials having useful properties.
Similar to the formation of a large array of compositions as described in U.S. Pat. No. 5,985,356, is a technique for forming an array of different compositions, including metal alloys wherein the individual components that form the composition are applied by thin film deposition as continuous concentration gradients across a sheet. J. J. Hanak, “The ‘Multiple-Sample Concept’ in Materials Research: Synthesis, Compositional Analysis and Testing of Entire Multicomponent Systems”, Journal of Materials Science 5 (1970) 964-971 discusses the development of multicomponent synthesis including the use of a technique of co-evaporating or co-sputtering two or more elements from different, physically separated sources onto a suitable substrate. In one experiment, almost the entire composition continuum of a given binary or ternary system was deposited on one substrate. Specimens made by the foregoing techniques have to be analyzed for chemical content point by point by existing chemical or physical methods. Thus the advantage gained by the synthesis technique was all but lost in the analytical methods. The article discloses that a unique computerized analytical method was developed based on the measurement of a simple extensive property common to all deposited films, namely, the thickness. In order to obtain analysis for the entire composition range the only required measurements are the two thickness measurements for a given binary system or three such measurements for a ternary system. The development of the computerized analysis is stated to have meant the removal of the main obstacle to the realization of the multiple sample concept. Goldfarb, et al., “Novel Sample Preparation Technique for the Study of Multiple Component Phase Diagrams”, Materials Letters 21 (1994) 149-154, provides a technique for alloy sample preparation based on thin film deposition, for a study of binary and ternary compositions. Thin elemental wedge-shaped layers of the components were gradually sputtered in an alternating manner to form a multi-layered structure. The samples obtained had compositions which depended upon the location of the substrate. Such samples, containing differently composed Au—Ag—Cu alloys were heat treated to promote formation of stable phases. The alloys formed were studied by x-ray diffraction and various microscopic techniques. The article demonstrates the advantages of the disclosed method over conventional bulk-based methods. A similar approach was taken to evaluate alternative thin-film dielectrics as described in Letters to Nature, “Discovery of a Useful Thin-film Dielectric Using a Composition-Spread Approach”, R. B. van Dover, et al., Nature (vol. 392) Mar. 12, 1998. In this article, a wide range of compositions were efficiently evaluated by using a technique of depositing a single film with a ternary composition spread on a sheet and evaluating the critical properties as a function of position on the sheet which is directly related to material composition using an automated tool, the continuous composition spread technique.
Different from new materials in which new chemical compounds are formed from reaction mixtures of distinct reaction elements or compounds, or alloys, which are solid solutions of two or more components, are composite materials, which typically comprise one, or more components arranged as unreacted mixtures or layers. Composite materials are widely used for industrial and consumer use and are formed based upon the idea that a mixture of components can yield a better property configuration than a single base component. Among the numerous objects which can be formed as composites, non-limiting samples include heterogeneous catalysts, adsorbents for gas or liquid separations and pigments. Heterogeneous catalysts, for example, are widely used for industrial processing and/or in consumer goods, such as, for example, as oxidation catalysts contained in catalytic converters of automobiles. As opposed to new compounds from deposited reactive layers, the chemical compositions which form the distinct deposited compounds of heterogeneous catalysts remain mostly distinct from the other compounds. The activity of particular catalysts, the selectivity to achieve the desired product, thermal, hydro and hydrothermal stabilities of the heterogeneous catalysts often depend upon the distinct layered configuration of the deposited metal, metal oxide or other compounds as well as the distinct composition of each layer and/or thickness of each layer which are deposited to form the heterogeneous catalytic material. Moreover, often the heterogeneous catalyst is supported on a metallic or ceramic support which although may be neutral with respect to the chemical reactants contacting the catalyst, may have a physical or chemical effect on the catalytic components in immediate contact or approximate to the support. Thus, for catalytic converters, cordierite honeycombs are typically coated with one or more washcoats of catalytic layers. It is not uncommon for the cordierite substrate to alter the catalytic properties of the layer or layers in contact or proximate contact with the substrate such that differences between contemplated and actual results achieved with the catalyst may disadvantageously exist.
According to U.S. Pat. Nos. 6,063,633; 6,333,196; and 6,514,764, assigned to the University of Houston, Tex., a multisample holder (support) e.g., a honeycomb or plate, or a collection of individual support particles, is treated with solutions/suspensions of catalyst ingredients to fill wells in plates, or to produce cells, spots, or pellets, holding each of a variety of combinations of the ingredients, is dried, calcined or otherwise treated as necessary to stabilize the ingredients in the cells, spots, or pellets, then is contacted with a potentially reactive feed stream or bath, e.g., to catalyze biochemical reactions catalyzed by proteins, cells, enzymes; gas oil, hydrogen plus oxygen, ethylene or other polymerizable monomer, propylene plus oxygen, or CC12F2 and hydrogen. The reaction occurring in each cell is measured, e.g., by infrared thermography, spectroscopic, electrochemical, photometric, thermal conductivity or other method of detection of products or residual reactants, or by sampling, e.g., by multistreaming through low volume tubing, from the vicinity of each combination, followed by analysis, e.g., spectral analysis, chromatography, etc., or by observing temperature change in the vicinity of the catalyst, e.g., by thermographic techniques, to determine the relative efficacy of the catalysts in each combination. Robotic techniques can be employed in producing the cells, spots, pellets, etc. These patents disclose that the process can be used to form and analyze a variety of catalysts including those for chemical and hydrocarbon conversions. Supports such as inert clays, zeolites, ceramics, carbon, plastics, e.g., reactive plastics, stable, nonreactive metals, or combinations of the foregoing can be used. The catalyst candidate precursors can be deposited onto the supports by any convenient technique, preferably by pipette or absorbing stamp (like a rubber stamp), or silkscreen.
In accordance with copending, commonly assigned U.S. Ser. No. 10/118,185, filed Apr. 8, 2002, there is disclosed a process for the preparation and use of a substrate having multiple samples of composite compositions provided thereon. The composite samples comprise one or more components coated onto a substrate in discrete regions of the substrate or in continuous concentration gradients covering large sections of the substrate and varying in concentration along one or more axes of the substrate. The substrate, if desired, can comprise part of the composite.
Drying of the components placed on the substrate, if necessary, can take place simultaneously after application of each component or subsequent to application of the final component. After deposition of the components is complete, composite samples containing one or more components attached to the substrate can then be removed with or without the underlying substrate layer and screened for useful properties. As such, the invention provides methods for the parallel synthesis of large numbers of novel composites. Analysis can then be done on each removed composite sample.
In a particularly useful embodiment for providing the library of composite compositions as disclosed therein; one or more of the component coatings are formed as a continuous gradient across the whole of the substrate. The gradient can be with respect to concentration or loading of a particular component or may vary in compositional differences. By applying a coating gradient across the substrate, it is possible to generate a composite library that contains all of the intermediate compositions or concentrations between a desired compositional or concentration range. Samples with any specific composition within the desired range can be tested from such a library by going to a specific location on the substrate sheet and testing at such location or cutting out the sample from the coated sheet. Thus, libraries of composite compositions with an exhaustive range of compositions can be prepared for one-component as well as multi-component compositions. Several overlapping gradients can be prepared to mimic complex multi-dimensional phase diagrams.
The embodiment of the invention disclosed in U.S. Ser. No. 10/118,185, where continuous gradients of coatings are applied across the substrate are exemplified as the gradient moves across a two-dimensional square sheet. In one configuration, the loading of a deposited component is increased as the gradient moves across the x-axis of the substrate sheet. In this case the loading changes only along the x-axis. In the second configuration, the minimum loading occurs at the corner of the sheet and increases as a function of both x and y. The coatings with continuous gradient concentrations can be prepared as either single-component or multi-component systems. Examples of libraries with these gradient coatings include the following: (1) Uniform coatings of one or more components can first be placed on the substrate sheet. In such case the composition of the entire surface would be the same. Subsequent to the application of the uniform coating, one or more gradient coatings such as those described above could be placed on top of the base coat. (2) The configuration may be prepared as a single-component system to examine the effect of concentration of a particular component on a composite. Such a technique is even more powerful when two different gradients are placed on the same surface. The minimum loading for the first component can be at one corner of the sheet while the minimum loading for the second component may be at either a neighboring corner or at the opposite corner of the sheet to create different combinations of the two components. Alternatively, the patterns for the two components may overlap one another, i.e. the minimum for both would occur at the same corner. (3) The configuration can also be used to place two different gradient coatings. Three unique orientations of the second gradient relative to the first are possible: (a) the minimum loading of the second component occurs at the same location as the minimum of the first component, therefore as the gradients move across the sheet, loading for both components increase, (b) the minimum loading for the second component occurs at an edge that is adjacent to the edge for the minimum loading for the first component. Therefore, the two patterns are 90° off relative to each other. (c) The minimum loading for the second component occurs at an edge that is opposite of the edge of the minimum loading for the first component, and therefore, the two patterns are 180° off relative to each other. While the libraries are not limited in terms of the numbers of components that can be applied, the gradient technique is quite powerful to yield a vast number of composite compositions even when using only one or two deposited components. The configuration as described above are just a few of the possible ones which can be applied.
The use of screen printing is a particularly useful technique to form gradient coatings. The appropriate screen to deliver a gradient coating can be produced by photolithographic techniques known in the art.
Once the gradient coatings have been applied to the substrate in the desired manner, it is important to be able to calculate the composition of any given spot on the gradient based on its location. A mathematical protocol disclosed in U.S. Ser. No. 10/118,185 has been devised for determining these compositions depending upon the coating gradient protocol which has been used. The method as developed in this copending application for the placement of gradient coatings onto a ceramic sheet has enabled many combinations of two or more materials to be formed and tested and has greatly enhanced the combinatorial screening of heterogeneous catalysts. However, the method has not been as effective for generating libraries containing all possible combinations that add up to a constant total in combinatorial systems containing three or more components.
Regardless of the use of the composite, there is an increasing need to rapidly test different compositions, configurations of compositional layers and/or relative concentrations of components with respect to each other. Accordingly, an enormous need still exists with respect to testing the numerous possible combinations of multiple materials used to form a composite or new composition. The variables for making a composite or new composition are still huge even if each component of the composite or composition is known and selected inasmuch as the arrangement (configuration) of layers, if used, and/or concentration of the individual components with respect to the other components still need to be tested for the desired properties which are sought.